We administered high doses of calcitriol (up to 32 micrograms per day) to an infant with malignant osteopetrosis, in an attempt to stimulate bone resorption. The patient was placed on a low-calcium diet to prevent hypercalcemia. Measures of bone turnover increased during calcitriol therapy; hydroxyproline excretion rose from 140 to 1358 micrograms per milligram of creatinine per 24 hours, with parallel increases in the ratio of calcium to creatinine in the urine, urinary gamma-carboxyglutamic acid, serum osteocalcin, and serum alkaline phosphatase. A pretreatment bone-biopsy specimen contained no osteoclasts with ruffled borders, a feature of active osteoclasts. After 11 days of calcitriol, ruffled borders were noted. After three months, numerous osteoclasts with ruffled borders and associated bony disruption were evident. Before therapy, the patient's monocytes were incapable of in vitro bone resorption, but after calcitriol, their resorptive capacity was increased to 3.3 times control levels. These data demonstrate that calcitriol increased bone mineral and matrix turnover in our patient. However, during the three months of calcitriol therapy there was only slight clinical improvement in her severe disease. Early and sustained treatment with calcitriol may be useful in osteopetrosis.

Osteocalcin is a major bone matrix protein with high affinity for hydroxyapatite. This property is conferred by several residues of the calcium-binding amino acid gamma-carboxyglutamate (Gla), which requires vitamin K for its biosynthesis. Because this protein may play a role in the local control of calcium deposition or removal in mineralized tissue, we measured circulating osteocalcin levels and urinary excretion of its breakdown product, Gla, in patients with osteoporosis and Paget's disease. Studies were conducted either on a metabolic ward or in ambulatory patients. Diagnoses were established by clinical and laboratory findings, and were confirmed by histological examination in 19 of 26 patients with osteoporosis. Mean urinary Gla excretion was increased (P less than 0.001) in patients with osteoporosis by 50% above the normal mean; serum osteocalcin, however, was not significantly different from normal. In Paget's disease patients, this pattern was reversed; serum osteocalcin levels were increased 3-fold (P less than 0.001), while urinary Gla excretion was consistently normal, regardless of the extent or activity of the disease. These data demonstrate that measurements of urinary Gla and serum osteocalcin may provide important insights into the metabolic derangements in these and other bone disorders.

The effects of highly purified human monocyte-derived interleukin-1 (IL-1) on bovine nasal cartilage breakdown were investigated. Cartilage degradation was determined by quantifying the fraction of total proteoglycan released from cartilage during 8 days of culture. The response appeared to be chondrocyte-dependent, for IL-1 stimulated proteoglycan (PG) release from living but not from dead (frozen-thawed) cartilage. IL-1 action on living cartilage was heat labile and concentration dependent, with significant effect at 5 U/ml and maximal effect at 10-20 U/ml. Kinetic studies showed significant stimulation of PG release by 3 days of incubation with 10 U/ml IL-1. Studies in which IL-1 was removed on day 1 or day 4 showed that the cartilage-degrading effect of this monokine was reversible. Although IL-1 caused little change in the Sepharose CL-2B chromatographic profile of released PGs using an associative elution buffer, a significant shift to lower mol wt was observed under dissociative conditions. To probe the mechanism of IL-1 action, cartilage samples were incubated with IL-1 in the presence of the protein synthesis inhibitor, cycloheximide, or the lysosomal membrane-stabilizing steroid, hydrocortisone. Cycloheximide at 5-10 micrograms/ml completely blocked IL-1-induced breakdown. One the other hand, 3 x 10(-7) M hydrocortisone had little or no effect on IL-1 action. IL-1 was also shown to stimulate the degradation of human articular cartilage.